High-dose intravenous immunoglobulin (IVIG) has been shown to be effective for the treatment of a variety of immune-mediated inflammatory diseases. Numerous mechanisms have been proposed to explain the mode of action of IVIG. In this application, we propose to investigate the molecular basis for the protective property of IVIG in the autoimmune blistering diseases pemphigus and pemphigoid. Pemphigus and pemphigoid are a group of potentially fatal organ specific autoimmune diseases. Pemphigus is characterized by intraepidermal blisters and epidermal-specific IgG autoantibodies. Pemphigoid is characterized by subepidermal blisters and autoantibodies against hemidesmosomal and extracellular matrix components in the basement membrane zone (BMZ). In this proposal, we will focus on three clinical entities: pemphigus foliaceus (PF), pemphigus vulgaris (PV), and bullous pemphigoid (BP). We will use well-characterized IgG passive transfer and active animal models for these diseases to test a hypothesis that infused WIG prevents IgG antibody-mediated blistering diseases by binding and blocking FcRn, the protection receptor for IgG catabolism, which leads to accelerated clearance of pathogenic IgG. In Aim 1, we will determine whether therapeutic doses of IVlG block blisters in experimental PF, PV, BP, and MMP. In Aim 2, we will determine whether the protective property of IVlG in these disease models depends on FcRn. We will induce skin disease in FcRn-deficient mice with IVIG treatment. In Aim 3, we will determine whether IgG Fc fragments can replace IVIG and FcRn inhibitory peptides are therapeutic. The overall goal of this project is to study the mechanisms of WIG action in autoantibody-mediated diseases and develop novel therapies to replace current immunosuppressive treatments, which confer severe side effects.